Pre-Activity Assessment/ Evaluation Form. Faculty. Program Agenda. Credit Designation. CE Information

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1 Pre-Activity Assessment/ Evaluation Form Pre-Activity Assessment Please take a moment to complete the pre-activity assessment prior to the start of the activity. Evaluation Form Please take a moment at the conclusion of the activity to complete the evaluation form in the back of the workbook. The on-site staff will collect the pre-activity assessment and evaluation forms at the conclusion of the activity. Thursday, September 14, :00pm-1:00pm Drury Lane Theatre & Conference Center 100 Drury Lane Oakbrook Terrace, L Faculty Program Agenda Michael B. Bottorff, PharmD, FCCP, FNLA, CLS Professor and Chair Department of Pharmacy Practice Manchester College of Pharmacy Fort Wayne, N 5 minutes ntroduction and Overview: The challenge of reducing hospitalization and readmission in HF 10 minutes Epidemiology and health-system burden of HF in the US 10 minutes Pathophysiology and risk factors of HF 10 minutes Updating the treatment of HF 15 minutes New frontiers in workup, monitoring, and treatment of HF 10 minutes Conclusions and Q&A CE nformation Credit Designation Target Audience This educational activity is directed toward hospital and health-system pharmacists and pharmacy technicians that manage patients with HF. Provider This activity is provided by Medical Learning nstitute, nc. Commercial Support Acknowledgment This activity is supported by educational grants from Novartis Pharmaceuticals Corporation and Relypsa, nc., a Vifor Pharma Company. Registered Pharmacy Designation The Medical Learning nstitute, nc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this application-based activity provides for 1.0 contact hour (0.10 CEU) of continuing pharmacy education credit. Universal Activity Number: L01-P Universal Activity Number: L01-T 1

2 Learning Objectives Disclosure Upon completion of this activity, the participant will be able to: Pharmacists Describe the high incidence and burden of HF including the risk of hospitalization and the need to meet quality metrics for the reduction of readmissions in HF Explain the complex pathophysiology and risk factors for HF ntegrate new classes of pharmacologic agents for HF into the current effective treatment paradigm Plan for the use of biomarkers and novel electronic monitoring technologies to work-up, monitor treatment follow-up, and medication adjustment in HF Pharmacy Technicians Explain the burden of and challenges faced in reducing hospitalization and readmission in HF Describe the types, causes, and signs and symptoms of HF dentify new classes of pharmacologic agents for HF Recognize new frontiers in workup, monitoring and treatment in HF Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any offlabel discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning nstitute nc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. The associates of Medical Learning nstitute nc, the accredited provider for this activity do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CPE activity for any amount during the past 12 months. Name of Planner/Manager Title Reported Financial Relationship Shelley Chun, PharmD Peer Reviewer Has nothing to disclose. Faculty Disclosures Disclaimer Michael B. Bottorff, PharmD, FCCP, FNLA, CLS, is on the Speakers' Bureau for Novartis, Pfizer/BMS Alliance, and Reliant/Sanofi Alliance. He does not intend to discuss any non-fda-approved or investigational use of any products/devices. The information provided at this CPE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this activity should be inferred. nstructions for Credit Heart Failure Treatment Options and Guidelines This activity is held in conjunction with the CHP Annual Meeting. To receive credit for this CPE activity, please take a few minutes to complete the pre-activity assessment and evaluation form and return it to the on-site coordinator. Your confirmation of reported participation will be ed to you within 4 weeks. You may also choose to complete this evaluation form off-site, return it by mail or fax to: Medical Learning nstitute, nc. 203 Main Street, Suite 249 Flemington, NJ (fax) Michael B. Bottorff, PharmD, FCCP, FNLA, CLS Professor and Chair Department of Pharmacy Practice Manchester College of Pharmacy Fort Wayne, N For questions regarding the accreditation of this activity, please contact Medical Learning nstitute, nc. at or ndane@mlicme.org. For pharmacists and pharmacists technicians, Medical Learning nstitute, nc. will accept your completed evaluation form up to 30 days following participation and will report your participation in this educational activity to the NABP ONLY if you provide your NABP e-profile number and date of birth. Within 6 weeks of participation, you will receive a confirmation and can then view your participation record at the NABP. 2

3 Heart Failure Objectives for the Pharmacist Know the general concepts about the epidemiology of heart failure Number of patients, high rate of hospitalizations, high mortality Explain the relationship between heart failure outcomes and neurohormonal imbalance Know how to initiate, titrate, monitor and adjust the following drugs Diuretics, ACE/ARB, beta blockers, aldosterone receptor antagonists, ARN, SDN/hydralazine, digoxin, ivabradine Know the difference between drugs that improve symptoms/hospitalizations vs those that improve survival Examine a patient medication profile and recommend AHA Class recommended therapy, discontinue Class therapies Heart Failure Patients in US (Millions) Epidemiology of Heart Failure in the US *Rich M. J Am Geriatric Soc. 1997;45: American Heart Association Heart and Stroke Statistical Update. American Heart Association Heart and Stroke Statistical Update. Heidenreich PA et al. Circulation. 2011;123(8): * More deaths from heart failure than from all forms of cancer combined 550,000 new cases/year 1 in 9 deaths in 2009 listed heart failure as a contributing cause Estimated costs exceed $30 billion each year The Paradox : ncreasing age of population ncrease in risk factors mproved post M survival Coronary artery disease Hypertension Diabetes Cardiomyopathy Valvular disease Pathologic Progression of CV Disease Myocardial injury Pathologic remodeling Neurohormonal stimulation Myocardial toxicity Low ejection fraction Symptoms: Dyspnea Fatigue Edema Sudden Death Death Pump failure Chronic heart failure Natriuretic peptide system 1 NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy Overactivation of the RAAS and SNS is Detrimental in HFrEF and Underpins the Basis of Therapy HFrEF SYMPTOMS & PROGRESSON The crucial importance of the RAAS is supported by the beneficial effects of ACEs, ARBs and MRAs 1 Benefits of β blockers indicate that the SNS also plays a key role 1 ACE: angiotensin-converting-enzyme inhibitor; Ang: angiotensin; ARB: angiotensin receptor blocker; AT 1R: angiotensin type 1 receptor; MRA: mineralocorticoid receptor antagonist; NPs: natriuretic peptides; NPRs: natriuretic peptide receptors; RAAS: renin-angiotensin-aldosterone system; SNS: sympathetic nervous system 1. McMurray et al. Eur Heart J 2012;33: ; Figure References: Levin et al. N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Kemp & Conte. Cardiovascular Pathology 2012;365 71; Schrier & Abraham. N Engl J Med 2009;341: Sympathetic nervous system Epinephrine Norepinephrine α 1, β 1, β 2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility Renin angiotensinaldosterone system Ang AT 1R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis Adapted from Cohn JN. N Engl J Med. 1996;335: Heart Failure: Neurohormonal mbalance Causes of Heart Failure Vasoconstriction Tachycardia Fluid retention Rev Cardiovasc Med. 2001;2(suppl 2):S2-S6. NE AT- Endothelin Aldosterone Vasopressin ANP BNP NO Bradykinin Prostacyclin Vasodilation Suppress sympathetic NS Suppress RAAS Natriuresis/diuresis Coronary artery disease (with or without M) Hypertension diopathic dilated cardiomyopathy Valvular disease (aortic stenosis, mitral regurgitation) Post-partum cardiomyopathy Viral cardiomyopathy Anticancer drugs (adriamycin) Heavy metal toxicity 3

4 Clinical Presentation Two Types of Heart Failure Left sided heart failure signs and symptoms DOE Bibasilar rales Orthopnea Pulmonary edema Tachypnea S 3 gallop Right sided heart failure signs and symptoms Abdominal pain Peripheral edema Nausea JVD Constipation Hepatomegaly Non-specific signs and symptoms Fatigue Tachycardia Weakness Cardiomegaly Systolic dysfunction Low ejection fraction Below 40-45% Largest group of HF patients All beneficial drug outcome trials All guidelines Diastolic dysfunction mpaired relaxation Similar symptoms Slightly less common Few outcome studies Chronic Congestive Heart Failure Evolution of Clinical Stages NORMAL No symptoms Normal exercise Normal LV fxn No symptoms Normal exercise Abnormal LV fxn Asymptomatic LV Dysfunction Compensated CHF Decompensated CHF No/minimal symptoms Exercise Abnormal LV fxn Symptoms Exercise Abnormal LV fxn Refractory CHF Symptoms not controlled with treatment Classification of HF: Comparison Between ACC/AHA HF Stage and NYHA Functional Class ACC/AHA HF Stage 1 NYHA Functional Class 2 A At high risk for heart failure but without structural heart disease or symptoms of heart failure (eg, patients with hypertension or coronary artery disease) B Structural heart disease but without symptoms of heart failure C Structural heart disease with prior or current symptoms of heart failure D Refractory heart failure requiring specialized interventions 1 Hunt SA et al. J Am Coll Cardiol. 2001;38: New York Heart Association/Little Brown and Company, Adapted from: Farrell MH et al. JAMA. 2002;287: Asymptomatic Symptomatic with moderate exertion Symptomatic with minimal exertion V Symptomatic at rest Goals in the Management of Heart Failure Stabilize the patient (improve symptoms and quality-of-life) Stabilize the disease (slow progression) Reduce hospitalizations Reduce mortality (prolong life) Physical activity Diet Na+ restriction Meals Fluid intake Non-pharmacologic Therapy Surgical correction of underlying processes Smoking cessation Adequate support and counseling Severe disease measures 4

5 Heart Failure Medications mprove Symptoms Diuretics Digoxin mprove Survival Beta-blockers ACE-inhibitors Mineralocorticoid receptor antagonists (MRA) Angiotensin receptor blockers (ARB s) ARN HCTZ. He complains of increasing weight gain (10 lbs over 2 weeks), bilateral ankle swelling, increased shortness of breath when walking up stairs He has a past medical history of hypertension, CAD (Hx M 3 yrs ago), and diabetes HCTZ 12.5mg po QD Atenolol 50mg po QD Diuretics in Heart Failure Loop Diuretics Thiazide diuretics possible for mild congestion Loop diuretics preferred for most patients Furosemide for the majority of patients Torsemide has better, more reliable absorption Less hospitalizations, lower cost of care (Clin Therapeutics 1999, ASCPT 2000) Metolazone reserved for apparent diuretic resistance Diuretic advantages Necessary for fluid control Synergistic effect with ACE-inhibitors Diuretic disadvantages Electrolyte disturbances (arrhythmogenic, dig toxicity) Potassium, magnesium depletion Hypovolemia, hypotension, renal dysfunction Worsening of the neurohormonal balance Thiazide-Like Diuretic Used in Combination with Loop Diuretics Pharmacological Therapy for Management of Stage C HFrEF Diuretics are recommended in patients with HFrEF with fluid retention C The target dose of diuretic in HFrEF is the dose that keeps patients at their dry weight; that is the weight where a patient is as symptom free as their heart failure will let them be. Many patients will monitor their daily weight and self-adjust their own loop diuretic therapy. HCTZ. He complains of increasing weight gain (10 lbs over 2 weeks), bilateral ankle swelling, increased shortness of breath when walking up stairs He has a past medical history of hypertension, CAD (Hx M 3 yrs ago), and diabetes HCTZ 12.5mg po QD Atenolol 50mg po QD 5

6 ACE in HFrEF HCTZ. He complains of increasing weight gain (10 lbs over 2 weeks), bilateral ankle swelling, increased shortness of breath when walking up stairs He has a past medical history of hypertension, CAD (Hx M 3 yrs ago), and diabetes D/C HCTZ 12.5mg po QD, initiate furosemide 40mg po QD Atenolol 50mg po QD mproved Symptoms (QoL), hospitalizations, and survival Altered/delayed remodeling of LV post-m Disadvantages Side effects (cough, angioedema, rash - captopril) Hypotension, reduce renal function, hyperkalemia Drugs Commonly Used for HFrEF (Stage C HF) Pharmacological Therapy for Management of Stage C HFrEF Diuretics Diuretics are recommended in patients with HFrEF with fluid retention C ACE nhibitors ACE inhibitors are recommended for all patients with HFrEF A ARBs ARBs are recommended in patients with HFrEF who are ACE inhibitor intolerant A ARBs are reasonable as alternatives to ACE inhibitor as first line therapy in HFrEF a A The addition of an ARB may be considered in persistently symptomatic patients with HFrEF on GDMT b A Routine combined use of an ACE inhibitor, ARB, and aldosterone antagonist is potentially harmful : Harm C HCTZ. He complains of increasing weight gain (10 lbs over 2 weeks), bilateral ankle swelling, increased shortness of breath when walking up stairs He has a past medical history of hypertension, CAD (Hx M 3 yrs ago), and diabetes Furosemide 40mg po qd Atenolol 50mg po QD Start Lisinopril 5mg po QD Risk of hyperkalemia and need for monitoring K and SCr at week 1, 4, and 8 when starting therapy Are all Beta Blockers Equally Beneficial n Heart Failure? 6

7 Recent Trials of Beta Blockers in Heart Failure Beta-Blocker Therapy Monitoring Beta-blocker Placebo * Hypotension Temporarily reduce vasodilator therapy f hypotension persists, decrease β- blocker dose % Mortality * * * Beta Blocker Therapy Fluid Retention Slow down the rate of dose titration Temporarily increase diuretic dose 5 0 CBS- MERT-HF CAPRCORN COPERNCUS BEST * P<0.05 Bisoprolol Metoprolol Carvedilol Carvedilol Bucindolol Bradycardia Reduce β- blocker dose to highest tolerable dose f bradycardia persists, discontinue β- blocker Beta Blockers Pharmacological Therapy for Management of Stage C HFrEF and Drugs Commonly Used for HFrEF (Stage C HF) Use of 1 of the 3 beta blockers proven to reduce mortality is recommended for all stable patients Beta Blockers Drug nitial Daily Dose (s) Maximum Dose(s) A Mean Doses Achieved in Clinical Trails Bisoprolol 1.25 mg once 10 mg once 8.6 mg/d (118) Carvedilol mg twice 50 mg twice 37 mg/d (446) Carvedilol CR 10 mg once 80 mg once Metoprolol succinate extended release (metoprolol CR/XL) 12.5 to 25 mg once 200 mg once 159 mg/d (447) HCTZ. He complains of increasing weight gain (10 lbs over 2 weeks), bilateral ankle swelling, increased shortness of breath when walking up stairs He has a past medical history of hypertension, CAD (Hx M 3 yrs ago), and diabetes Furosemide 40mg po qd Atenolol 50mg po QD (d/c and initiate carvedilol 12.5mg bid) Lisinopril 5mg po QD Anti-Aldosterone Agents Role of Aldosterone Receptor Antagonists in Heart Failure Spironolactone O Eplerenone O O O SCOCH 3 COOCH 3 Binding to mineralocorticoid receptors Partial affinity for glucocorticoid receptors nhibition of P450 enzymes in endocrine organs nduction of P450 enzymes in the liver Complex metabolism Greater specificity for mineralocorticoid receptors Fewer progestational and anti-androgenic actions No effect on P450 hydroxylases in endocrine organs Minimal increase in liver P450 enzymes 7

8 Aldosterone Antagonists Pharmacological Therapy for Management of Stage C HFrEF and Drugs Commonly Used for HFrEF (Stage C HF) Aldosterone receptor antagonists are recommended in patients with NYHA class -V HF who have LVEF < 35% Aldosterone receptor antagonists are recommended in patients following an acute M who have LVEF <40% with symptoms of HF or DM nappropriate use of aldosterone receptor antagonists may be harmful Aldosterone Antagonists : Harm Drug nitial Daily Dose (s) Maximum Dose(s) Mean Doses Achieved in Clinical Trails Spironolactone 12.5 to 25 mg once 25 mg once or twice 26 mg/d (424) Eplerenone 25 mg once 50 mg once 42.6 mg/d (445) A B B HCTZ. He complains of increasing weight gain (10 lbs over 2 weeks), bilateral ankle swelling, increased shortness of breath when walking up stairs He has a past medical history of hypertension, CAD (Hx M 3 yrs ago), and diabetes Furosemide 40mg po qd Carvedilol 12.5mg po bid Lisinopril 5mg po QD nitiate spironolactone 25mg po QD A-Heft Trial: Primary Endpoint All individual components of the primary composite endpoint were significantly improved with SDN-hydralazine therapy, namely death, first hospitalization for heart failure, and change in the quality-of-life score (a larger negative score indicates a better quality of life). Pharmacological Therapy for Management of Stage C HFrEF and Drugs Commonly Used for HFrEF (Stage C HF) Hydralazine and sosorbide Dinitrate The combination of hydralazine and isosorbide dinitrate is recommended for African Americans, with NYHA class -V HFrEF on GDMT A A combination of hydralazine and isosorbide dinitrate can be useful in patients with HFrEF who cannot given ACE inhibitors or ARBs a B Hydralazine & sosorobide Dinitrate Drug nitial Daily Dose (s) Maximum Dose(s) Mean Doses Achieved in Clinical Trails Fixed dose combination (423) 37.5 mg hydralazine/ 75 mg hydralazine/ ~175 mg hydralazine/ 20 mg isosorbide 40 mg isosorbide 90 mg isosorbide Dinitrate 3 times daily Dinitrate 3 times daily Dinitrate daily Hydralazine and Hydralazine: 25 to 50 mg, Hydralazine: 300mg daily sosorbide Dinitrate (448) 3 or 4 times daily and isosorbide in divided doses and Dinitrate: 20 to 30 mg 3 or 4 times isosorbide Dinitrate 120 mg daily daily in divided doses Presented at AHA Medical Therapy for Stage C HFrEF: Magnitude of Benefit Demonstrated in RCTs Digoxin in HFrEF: Mortality 50 GDMT RR Reduction in Mortality NNT for Mortality Reduction (Standardized to 36 mo) RR Reduction in HF Hospitalizations ACE inhibitor or ARB 17% 26 31% Beta blocker 34% 9 41% Aldosterone antagonist 30% 6 35% Hydralazine/nitrate 43% 7 33% % Placebo n=3403 DGOXN n=3397 p = 0.8 DG Months 48 N Engl J Med 1997;336:525 8

9 Association of Serum Digoxin Concentration and Outcomes Digoxin Clinical Uses Mortality (% at Mean of 37 months) 6.3% (p<0.05) 2.6% 11.8% (p<0.05) AF with rapid ventricular response CHF refractory to other drugs _ Should be combined with other drugs One Month SDC (ng/ml) Rathore et al, JAMA 2003:289:871. Pharmacologic Therapy for Management of Stage C HFrEF (Continued) Neprilysin nhibition Potentiates Actions of Endogenous Vasoactive Peptides that Counter Maladaptive Mechanisms in Heart Failure Digoxin Digoxin can be beneficial in patients with HFrEF a B Endogenous vasoactive peptides (natriuretic peptides, adrenomedullin, bradykinin, substance P, calcitonin gene-related peptide) Neurohormonal activation Vascular tone Cardiac fibrosis, hypertrophy Sodium retention Neprilysin Neprilysin inhibition nactive metabolites LCZ696 Mechanism of Action PARADGM-HF: Study Design Randomization Single-blind run-in period Double-blind period LCZ mg BD Enalapril 10 mg BD 100 mg BD LCZ mg BD (1:1 randomization) Enalapril 10 mg BD 2 weeks 1-2 weeks 2-4 weeks 9

10 PARADGM HF Trial Efficacy Results PARADGM-HF: Effect of LCZ696 vs Enalapril on Secondary Endpoints Primary Endpoint Death from Any Cause LCZ696 (n=4187) Enalapril (n=4212) Treatment effect P Value KCCQ clinical summary score at 8 months 2.99 ± ± (0.63, 2.65) New onset atrial fibrillation 84/2670 (3.2%) 83/2638 (3.2%) Hazard ratio 0.97 (0.72,1.31) 0.84 Death from CV Causes: 13.3% vs 16.5%; HR 0.8 ( ), p<0.001 First Hospitalization for HF: 12.8% vs 15.6%, HR 0.79 ( ), p<0.001 Change in quality of life: ± 0.36 vs ± 0.36 HR 1.64 ( ); p= Protocol-defined decline in renal function 94/4187 (2.3%) 108/4212 (2.6%) Hazard ratio 0.86 (0.65, 1.13) 0.28 PARADGM-HF: Adverse Events PARADGM-HF: Summary of Findings LCZ696 (n=4187) Prospectively identified adverse events Enalapril (n=4212) P Value Symptomatic hypotension < Serum potassium > 6.0 mmol/l Serum creatinine 2.5 mg/dl Cough < Discontinuation for adverse event Discontinuation for hypotension NS Discontinuation for hyperkalemia NS Discontinuation for renal impairment Angioedema (adjudicated) Medications, no hospitalization 16 9 NS Hospitalized; no airway compromise 3 1 NS Airway compromise n heart failure with reduced ejection fraction, when compared with recommended doses of enalapril: LCZ696 was more effective than enalapril in... Reducing the risk of CV death and HF hospitalization Reducing the risk of CV death by incremental 20% Reducing the risk of HF hospitalization by incremental 21% Reducing all-cause mortality by incremental 16% ncrementally improving symptoms and physical limitations LCZ696 was better tolerated than enalapril... Less likely to cause cough, hyperkalemia or renal impairment Less likely to be discontinued due to an adverse event More hypotension, but no increase in discontinuations Not more likely to cause serious angioedema Current treatment ACEi ARB Not on ACEi or ARB ACEi ARB Not on ACEi or ARB ACEi ARB Not on ACEi or ARB Current dose Patients receiving a total daily dose of >10mg of enalapril or therapeutically equivalent doses of another ACEi, for example 2 : Lisinopril >10mg Ramipril >5mg Patients receiving a total daily dose of < 10mg of enalapril or therapeutically equivalent doses of another ACEi, for example 2 : Lisinopril < 10mg Ramipril < 5 mg Patients receiving a total daily dose of >160mg of valsartan or therapeutically equivalent doses of another ARB, for example 2 : Losartan >50mg Olmesartan >10mg Patients receiving a total daily dose of < 160mg of valsartan or therapeutically equivalent doses of another ARB, for example 2 : Losartan <50mg Olmesartan <10mg Not currently taking ACEis or ARBs Recommended treatment Stop ACEi 36 hours before starting sacubitril/ valsartan Stop ACEi 36 hours before starting sacubitril/ valsartan Start sacubitril/valsartan at the recommended dose of 49/51 mg twice daily Start sacubitril/ valsartan at the recommended dose of 24/26mg twice daily Double the dose after 2 to 4 weeks to 49/51 mg twice daily, as tolerated by the patient Start sacubitril/valsartan at the recommended dose of 49/51 mg twice daily Start sacubitril/ valsartan at the recommended dose of 24/26mg twice daily Start sacubitril/ valsartan at the recommended dose of 24/26mg twice daily Double the dose after 2 to 4 weeks to 49/51 mg twice daily, as tolerated by the patient Double the dose after 2 to 4 weeks to 49/51 mg twice daily, as tolerated by the patient Double the dose of sacubitril/valsartan after 2 to 4 weeks, as tolerated by the patient, to reach the Target maintenance dose of 97/103 mg twice daily Double the dose of sacubitril/ valsartan after 2 to 4 weeks, as tolerated by the patient, to reach the Target maintenance dose of 97/103 mg twice daily Double the dose of sacubitril/valsarta n after 2 to 4 weeks, as tolerated by the patient, to reach the Target maintenance dose of 97/103 mg twice daily % Decrease in Mortality 0% 10% 20% 30% 40% Angiotensin Neprilysin nhibition With LCZ696 Doubles Effect on Cardiovascular Death of Current nhibitors of the Renin-Angiotensin System Angiotensin receptor blocker 15% Effect of ARB vs placebo derived from CHARM-Alternative trial Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial Effect of LCZ696 vs ACE inhibitor derived from PARADGM-HF trial ACE inhibitor 18% 20% Angiotensin neprilysin inhibition 10

11 Optimal mplementation of ARN in Heart Failure nevitable delay for implemention into practice of newly established therapies Cost-effectiveness Analysis of Sacubitril/Valsartan vs Enalapril in Patients with Heart Failure and Reduced Ejection Fraction Estimated 84% of U.S. patients with HFrEF as candidates for ARN therapy Optimal implementation would: Prevent 28,484 deaths per year 12 month NNT 80 Tornado DiagramUnivariate sensitivity analyses evaluating the effect of each variable s uncertainty on an overall cost-effectiveness ratio. The central black line represents the base-case analysis. None of the analyses lead to an incremental cost-effectiveness ratio greater than $ per quality-adjusted life-year (QALY). HR indicates hazard ratio. JAMA Cardiol. Published online June 22, doi: /jamacardio Copyright 2016 American Medical Association. All rights reserved. Fonarow GC et al. JAMA 2016 Date of download: 7/14/2016 vabradine: Mechanism of Action Primary Objective To evaluate whether the f inhibitor ivabradine improves cardiovascular outcomes in patients with: 1. Moderate to severe chronic heart failure 2. Left ventricular ejection fraction 35% 3. Heart rate 70 bpm in sinus rhythm 4. Best recommended therapy Swedberg K, et al. Eur J Heart Fail. 2010;12: Study Design Effect of vabradine on Outcomes Endpoints Hazard ratio 95% C p value Screening 7 to 30 days vabradine 5 mg bid Matching placebo, bid vabradine 7.5/5/2.5 mg bid according to HR and tolerability D0 D14 D28 M4 3.5 years Every 4 months Primary composite endpoint (CV death or hospital admission for worsening HF) 0.82 [0.75;0.90] p< All-cause mortality 0.90 [0.80;1.02] p=0.092 Death from heart failure 0.74 [0.58;0.94] p=0.014 All-cause hospital admission 0.89 [0.82;0.96] p=0.003 Any CV hospital admission 0.85 [0.78;0.92] p= CV death/hospital admission for HF or non-fatal M 0.82 [0.74;0.89] p< Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81 Swedberg K, et al. Lancet. 2010;376(9744):

12 AHA HF Update 2016 Recommendations for Renin-Angiotensin System nhibition with ACE nhibitor or ARB or ARN The clinical strategy of inhibition of the renin-angiotensin system with ACE inhibitors (Level of Evidence: A) (9-14), OR ARBs (Level of Evidence: A) (15-18), OR ARN (Level of Evidence: B-R) (19) in conjunction with ACE: A evidence based beta blockers (20-22), and aldosterone antagonists in ARB: A selected patients (23, 24), is recommended for patients with chronic HFrEF to reduce morbidity and mortality. ARN: B-R n patients with chronic symptomatic HFrEF NYHA class or who tolerate an ACE inhibitor or ARB, replacement by an ARN is ARN: B-R recommended to further reduce morbidity and mortality (19). ARN should not be administered concomitantly with ACE inhibitors or : Harm B-R within 36 hours of the last dose of an ACE inhibitor (31, 32) ARN should not be administered to patients with a history of angioedema. : Harm C-EO Recommendations for vadradine Recommendation COR LOE Symptomatic (NYHA class, ) stable chronic HFrEF (LVEF < 35%) who are receiving GDEM, including a beta blocker at maximum tolerated dose, a B-R and who are in sinus rhythm with heart rate of 70 bpm or greater at rest (37-40) HCTZ. He complains of increasing weight gain (10 lbs over 2 weeks), bilateral ankle swelling, increased shortness of breath when walking up stairs He has a past medical history of hypertension, CAD (Hx M 3 yrs ago), and diabetes Furosemide 40mg qd Carvedilol 12.5mg bid D/C Lisinopril 5mg po QD, wait 36 hr, initiate sacubitril/valsartan 50mg po BD Spironolactone 25mg po QD July 2016 HCTZ. He complains of increasing weight gain (10 lbs over 2 weeks), bilateral ankle swelling, increased shortness of breath when walking up stairs He has a past medical history of hypertension, CAD (Hx M 3 yrs ago), and diabetes Furosemide 40mg qd D/C Pioglitazone 45mg po QD Carvedilol 12.5mg bid D/C Diltiazem CR 240mg po QD D/C Lisinopril 5mg po QD, wait 36 hr, initiate sacubitril/valsartan 50mg po BD Spironolactone 25mg po QD What drug improves survival in heart failure with preserved systolic function (HFpEF)? Clinical Trials Showing mprovement in Morbidity/Mortality in HFpEF 12

13 Treatment of HFpEF Systolic and diastolic blood pressure should be controlled according to published clinical practice guidelines B Diuretics should be used for relief of symptoms due to volume overload C Coronary revascularization for patients with CAD in whom angina or demonstrable myocardial ischemia is present a C despite GDMT Management of AF according to published clinical practice guidelines for HFpEF to improve symptomatic HF a C Use of beta-blocking agents, ACE inhibitors, and ARBs for hypertension in HFpEF a C ARBs might be considered to decrease hospitalizations in HFpEF b B Nutritional supplementation is not recommended in HFpEF : No Benefit C 13